A Ph.D. biophysics from Johns Hopkins University (JHU), a MD from the University of Maryland (UMSOM), with postdoctoral clinical and research training in gerontology at JHU and NIA/GRC, and a NIA KO8 with postdoctoral clinical and research training in gerontology prepared the candidate for an academic career in gerontology. The candidate, an Associate Professor of Medicine at the UMSOM has 10 years of experience performing patient oriented research into the effects of weight loss and aerobic exercise training (AEX) on lipoprotein and glucose metabolism, and cardiovascular function in older men and women. The candidate directs clinical research at the BVAMC GRECC, is PI on a VA Merit Review grant, and co-PI on the UMSOM Pepper Center. The candidate has mentored 17 trainees in patient oriented research. Receipt of this K24 award will provide the candidate additional protected time for research and mentoring of gerontology MD fellows, postdoctoral Ph.D. fellows, and other trainees in patient oriented clinical investigations. The candidate's long term goal is to establish a nationally recognized center of excellence for research into gene-environment interactions and their influence on the prevention and treatment of cardiovascular diseases (CVD) in the elderly. Research: Prior studies demonstrate that the angiotensin converting enzyme (ACE) DD gene variant present in 25-30 percent of the population increases the risk for hypertension, stroke and cardiovascular disease. The study hypothesis is that in older hypertensive individuals, the ACE DD polymorphism will blunt the beneficial effects of AEX on BP, lipoprotein and glucose metabolism, and cardiovascular function compared to individuals with the ACE ID and II genotypes. This hypothesis will be tested in a clinical trial that will compare the effects of 6 months of AEX on BP, the BP response to mental stress (cardiovascular reactivity), metabolic function (lipoproteins, glucose clamp) and endothelial function in older hypertensives with the ACE DD versus ACE ID and II genotypes. Trainees will participate in all aspects of this research and learn how to design and implement clinical investigations that enhance our knowledge of gene-environmental interactions in moderating the effectiveness of AEX in lowering BP, and in improving metabolic and cardiovascular function in older hypertensive patients. This research may lead to targeted lifestyle and pharmacologic therapies based on genotype to treat hypertension and CVD in older patients.